We seek to elucidate the interactive roles that atherosclerosis and Abeta play in the pathogenesis of co-morbid Alzheimer's disease (AD) and vascular dementia. Although, most of the field's efforts have been focused on the role of LDL, ApoE and their receptors play in AD pathogenesis, we have obtained evidence that APP/Abeta alters the expression and localization of the LDLR, such that it becomes concentrated in single perinuclear aggregate, rather than sorting to the cell surface. Other experiments suggest that Abeta induces a general defect in the MT network that likely leads to the mis-localization of some, but not all membrane proteins, including the LDLR, potentially rendering it (them) less active. We therefore propose to Test the Hypotheses that 1. APP/Abeta affects LDLR expression and intracellular localization. 2. Abeta-induced LDLR mis-localization leads to LDLR functional deficits, hyperlipidemia and atherosclerosis. The proposed experiments are significant because they may allow us to conclude that one reason why atherosclerosis, especially in the brain so often accompanies AD is because it is promoted by LDLR functional deficits induced by Abeta. Furthermore, the differences in affinity/activation of the different isoforms of ApoE for LDLR may be made more acute when the LDLR is less active, thus accounting in part for the increased risk of AD imparted by ApoE4. These findings and conclusions form the foundation for a comprehensive series of experiments to test the above hypotheses and determine whether Abeta induces the mis-sorting and functional inactivity of other important neuronal and non-neuronal proteins in the AD, particularly, growth factor receptors and the insulin receptor.

Public Health Relevance

With 5 million patients nationwide and an annual cost of $140 billion and rising rapidly, Alzheimer's is a critical Health problem. Often Alzhimer's and brain atherosclerosis occur in the same patient. We have discovered a possible reason for the co-occurrence of vascular brain disease and Alzheimer's disease. Specifically we have found the Alzheimer Abeta peptide that in pathogenic form causes the neuronal damage and cognitive deficits of Alzheimer's disease also prevents the Low Density Lipoprotein Receptor from reaching the cell surface. The LDLR plays an essential role in bringing cholesterol into the cell and thus allowing the cell to function and also preventing buildup of LDL cholesterol in the blood and other fluids where it cause atherosclerosis. These results will be followed up to confirm them and establish the mechanism by which this damage to LDLR occurs. Such knowledge is essential for developing drugs against age- related Alzheimer's and vascular dementia.

National Institute of Health (NIH)
National Institute on Aging (NIA)
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Petanceska, Suzana
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University of South Florida
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Hamlett, Eric D; Ledreux, Aurélie; Potter, Huntington et al. (2018) Exosomal biomarkers in Down syndrome and Alzheimer's disease. Free Radic Biol Med 114:110-121
Caneus, Julbert; Granic, Antoneta; Rademakers, Rosa et al. (2018) Mitotic defects lead to neuronal aneuploidy and apoptosis in frontotemporal lobar degeneration caused by MAPT mutations. Mol Biol Cell 29:575-586
Freund, Ronald K; Gibson, Emily S; Potter, Huntington et al. (2016) Inhibition of the Motor Protein Eg5/Kinesin-5 in Amyloid ?-Mediated Impairment of Hippocampal Long-Term Potentiation and Dendritic Spine Loss. Mol Pharmacol 89:552-9
Potter, Huntington; Granic, Antoneta; Caneus, Julbert (2016) Role of Trisomy 21 Mosaicism in Sporadic and Familial Alzheimer's Disease. Curr Alzheimer Res 13:7-17
Potter, Huntington (2016) Beyond Trisomy 21: Phenotypic Variability in People with Down Syndrome Explained by Further Chromosome Mis-segregation and Mosaic Aneuploidy. J Down Syndr Chromosom Abnorm 2:
Potter, Huntington (2015) Kinesin light chain-1 variant E disrupts axonal transport and A? generation in Alzheimer's disease (comment on DOI 10.1002/bies.201400131). Bioessays 37:118
Hartley, Dean; Blumenthal, Thomas; Carrillo, Maria et al. (2015) Down syndrome and Alzheimer's disease: Common pathways, common goals. Alzheimers Dement 11:700-9
Potter, Huntington (2014) David H. Dressler 1941-2014. Nat Genet 46:1044
Ari, Csilla; Borysov, Sergiy I; Wu, Jiashin et al. (2014) Alzheimer amyloid beta inhibition of Eg5/kinesin 5 reduces neurotrophin and/or transmitter receptor function. Neurobiol Aging 35:1839-49
Granic, Antoneta; Potter, Huntington (2013) Mitotic spindle defects and chromosome mis-segregation induced by LDL/cholesterol-implications for Niemann-Pick C1, Alzheimer's disease, and atherosclerosis. PLoS One 8:e60718

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